Contribution of efflux to colistin heteroresistance in a multidrug resistant Acinetobacter baumannii clinical isolate

Machado, Diana; Antunes, Jéssica; Simões, Ana; Perdigão, João; Couto, Isabel; McCusker, Matthew P.; Martins, Marta; Portugal, Isabel; Pacheco, Teresa; Batista, Judite; Toscano, Cristina; Viveiros, Miguel

doi:10.1099/jmm.0.000741

Cited by 37 publications

(32 citation statements)

References 43 publications

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“…Two studies proved that efflux pumps could confer heteroresistance to colistin in Enterobacter spp. and A. baumannii (8,20). In contrast, Chambers and Sauer showed that the MerR-like regulator BrlR could impair P. aeruginosa tolerance to colistin (39).…”

Section: Colistin (Hetero)resistance In Pseudomonas Aeruginosamentioning

confidence: 99%

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Resistance and Heteroresistance to Colistin in Pseudomonas aeruginosa Isolates from Wenzhou, China

Lin

Fang

et al. 2019

Antimicrob Agents Chemother

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The goal was to investigate the mechanisms of colistin resistance and heteroresistance in Pseudomonas aeruginosa clinical isolates. Colistin resistance was determined by the broth microdilution method. Colistin heteroresistance was evaluated by population analysis profiling. Time-kill assays were also conducted. PCR sequencing was performed to detect the resistance genes among (hetero)resistant isolates, and quantitative real-time PCR assays were performed to determine their expression levels. Pulsed-field gel electrophoresis and multilocus sequence typing were performed. Lipid A characteristics were determined via matrix-assisted laser desorption–ionization time of flight mass spectrometry (MALDI-TOF MS). Two resistant isolates and 9 heteroresistant isolates were selected in this study. Substitutions in PmrB were detected in 2 resistant isolates. Among heteroresistant isolates, 8 of 9 heteroresistant isolates had nonsynonymous PmrB substitutions, and 2 isolates, including 1 with a PmrB substitution, had PhoQ alterations. Correspondingly, the expression levels of pmrA or phoP were upregulated in PmrB- or PhoQ-substituted isolates. One isolate also found alterations in ParRS and CprRS. The transcript levels of the pmrH gene were observed to increase across all investigated isolates. MALDI-TOF MS showed additional 4-amino-4-deoxy-l-arabinose (l-Ara4N) moieties in lipid A profiles in (hetero)resistant isolates. In conclusion, both colistin resistance and heteroresistance in P. aeruginosa in this study mainly involved alterations of the PmrAB regulatory system. There were strong associations between mutations in specific genetic loci for lipid A synthesis and regulation of modifications to lipid A. The transition of colistin heteroresistance to resistance should be addressed in future clinical surveillance.

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Section: Colistin (Hetero)resistance In Pseudomonas Aeruginosamentioning

confidence: 99%

“…Colistin heteroresistance has been described (6). Multiple studies have indicated that the presence of this phenotype may account for unexplained treatment failures (7)(8)(9).…”

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Resistance and Heteroresistance to Colistin in Pseudomonas aeruginosa Isolates from Wenzhou, China

Lin

Fang

et al. 2019

Antimicrob Agents Chemother

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“…18 According to the results of antibiotic susceptibility, isolates were classified to MDR, XDR and PDR according to the criteria previously reported. 20…”

Section: Mic Determination Of Colistin Antibioticmentioning

confidence: 99%

<p>Prevalence and Some Possible Mechanisms of Colistin Resistance Among Multidrug-Resistant and Extensively Drug-Resistant <em>Pseudomonas aeruginosa</em></p>

El-Baky

Masoud

Mohamed

et al. 2020

IDR

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Background and Aim: The emergence of colistin-resistant strains is considered a great threat for patients with severe infections. Here, we investigate the prevalence and some possible mechanisms of colistin resistance among multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa (P. aeruginosa). Methods: Antimicrobial susceptibility was performed using disc diffusion methods while colistin resistance was detected by agar dilution method. Possible mechanisms for colistin resistance were studied by detection of mcr-1 and mcr-2 genes by conventional PCR, detection of efflux mechanisms using Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP), studying outer membrane protein profile and Lipopolysaccharide (LPS) profile of resistant isolates. Results: It was found that MDR and XDR represented 96% and 87% of the isolated P. aeruginosa, respectively, and colistin resistance represented 21.3%. No isolates were positive for mcr-2 gene while 50% of colistin-resistant isolates were positive for mcr-1. Efflux mechanisms were detected in 3 isolates. Protein profile showed the presence of a band of 21.4 KDa in the resistant strains which may represent OprH while LPS profile showed differences among colistin-resistant mcr-1 negative strains, colistin-resistant mcr-1 positive strains and susceptible strains. Conclusion: The current study reports a high prevalence of colistin resistance and mcr-1 gene in P. aeruginosa strains isolated from Egypt that may result in untreatable infections. Our finding makes it urgent to avoid unnecessary clinical use of colistin.

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“…and NADH quinone oxidoreductase in E. coli. The activity of the enzyme is likely to be higher in the bacteria with colistin resistance mechanisms different from those involving modification of the lipopolysaccharides [43][44][45][46][47][48][49] . In Europe, the incidence of colistin resistant A. baumannii in intensive care units reached over 23% due to different mechanisms of resistance such as alterations in the lipopolysaccharide (LPS) as well as acquistion of mcr genes 50 .…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens

Blasco

Ambroa

Trastoy

et al. 2020

Sci Rep

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The emergence of multidrug resistant (MDR) pathogenic bacteria is jeopardizing the value of antimicrobials, which had previously changed the course of medical science. In this study, we identified endolysins ElyA1 and ElyA2 (GH108-PG3 family), present in the genome of bacteriophages Ab1051Φ and Ab1052Φ, respectively. The muralytic activity of these endolysins against MDR clinical isolates (Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae) was tested using the turbidity reduction assay. Minimal inhibitory concentrations (MICs) of endolysin, colistin and a combination of endolysin and colistin were determined, and the antimicrobial activity of each treatment was confirmed by time kill curves. Endolysin ElyA1 displayed activity against all 25 strains of A. baumannii and P. aeruginosa tested and against 13 out of 17 strains of K. pneumoniae. Endolysin ElyA2 did not display any such activity. The combined antimicrobial activity of colistin and ElyA1 yielded a reduction in the colistin MIC for all strains studied, except K. pneumoniae. These results were confirmed in vivo in G. mellonella survival assays and in murine skin and lung infection models. In conclusion, combining colistin (1/4 MIC) with the new endolysin ElyA1 (350 µg) enhanced the bactericidal activity of colistin in both in vitro and in vivo studies. This will potentially enable reduction of the dose of colistin used in clinical practice.

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Contribution of efflux to colistin heteroresistance in a multidrug resistant Acinetobacter baumannii clinical isolate

Abstract: This study shows that efflux activity contributes to colistin heteroresistance in an MDR A. baumannii clinical isolate. The use of efflux inhibitors as adjuvants of the therapy can resensitize A. baumannii to colistin and prevent the emergence of drug resistance.

Cited by 37 publications

References 43 publications

Resistance and Heteroresistance to Colistin in Pseudomonas aeruginosa Isolates from Wenzhou, China

Resistance and Heteroresistance to Colistin in Pseudomonas aeruginosa Isolates from Wenzhou, China

<p>Prevalence and Some Possible Mechanisms of Colistin Resistance Among Multidrug-Resistant and Extensively Drug-Resistant <em>Pseudomonas aeruginosa</em></p>

In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens

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